Certain ethers of open chain terpenoids as insect control agents

ABSTRACT

Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

limited States Patent Bowers Dec. 3, 1974 CERTAIN ETHERS OF OPEN CHAIN [56] References Cited TERPENOIDS AS INSECT CONTROL UNITED STATES PATENTS AGENTS 3,655,700 4/1972 Siddall 260/4109 Inventor: William S. Bowers, Bowie, Md.

Assignee: The United States of America as represented by the Secretary of Agriculture, Washington, DC.

Filed: May 23, 1973 Appl. No.2 363,295

Related US. Application Data Division of Ser. No. 78,577, Oct. 6, 1970, abandoned.

US. Cl 424/342, 424/278, 424/314,

424/DIG. 12, 260/340.9, 260/348 R,

Int. Cl AOln 9/24 Field of Search 424/342, DIG. 12; 2 60/61}, 260/4109 OTHER PUBLICATIONS Borkovec, A., Insect Chemosterilants, Vol. VII, (1966), PP. 61-63.

Primary ExaminerVincent D. Turner Attorney, Agent, or FirmM. Howard Silverstein; Max D. Hensley; William F. Scott 6 Claims, No Drawings CERTAIN ETHERS OF OPEN CHAIN TERPENOIDS AS INSECT CONTROL AGENTS This is a division of application Ser. No. 78,577 filed Oct. 6. 1970 now abandoned. I

A nonexclusive, irrevocable, royaltyfree license in the invention herein described throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America.

This invention relates to insect control and more particularly to compounds and to the preparation of compounds that have high juvenile hormone activity and which are highly ovicidal to insect eggs.

There is considerable concern throughout the world about the persistence of many insecticides and insecticide residues in our environment and the potential hazard that these materials represent to human populations. in addition, many species of insect pests have become resistant or immune to many of the insecticides on the market. Thus, more selective chemicals are required which will not pose a threat to human populations and to which the insects will not develop resistance.

The compounds of the present invention should be suitable replacements for the insecticides now being used to control stored product insects and many social pests such as fireants and termites. in addition, it may be feasible to use these compounds in field applications to control a wide variety of insects, the toxicity of the compounds to vertebrates should be insignificant, and the cost to produce them commercially should be very competitive with that of well known insecticides.

One object of this invention is to provide a means for achieving. selective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insect maturation when applied topically, when fed to insects or when applied in a vapor state as a fumigant, to an insect in an immature stage of growth.

A further object of this invention is to provide compounds that adversely affect the biological function of insects, particularly their ability to mature to an adult stage.

In general, according to the present invention the terpenoid ethers and their corresponding epoxides are synthesized and found to prevent insect maturation when applied to immature stages of several species of insects by topical application, by feeding or by fumigation (exposure to vapor). Thus an immature insect exposed to these compounds is unable to metamorphose into a normal adult. Topical application of as little as 10.0 nanograms (0.01 pg) of the more active compounds in this series is sufficient to prevent metamorphosis. The insect which emerges from the treated pupa retains immature genitalia which preclude copulation and reproduction. The insects die shortly after molting to this adultoid condition. Also, when used as a vapor or as a dip treatment for eggs the compounds drastically reduce egg hatch.

The compounds of this invention having the following general formula.

wherein Y is R is a straight chain alkyl containing from l-2 carbon atoms such as CH CH Cl-l x is a number from i to 2, and

Z is one of the following groups:

CH CH O(Cl-ihd 2),,CH in which n is O3;

CH COO(CH ),,CH in which n is 0-1;

in which n is 0-3.

The terpenoid portions of the compounds were. prepared in part by the Marc Julia synthesis [Bull. Soc. Chem. France 1072, (1960)] as outlined below.

Oxidation was performed with chromic acid solution in acetone [1. Chem. Soc. 2548, (l953)] The vinyl alcohols are prepared by the grignard reaction with vinyl magnesium bromide (or chloride) in tetrahydrofuran.

The vinyl alcohols were converted to the allylic bromides by treatment with hydrogen bromide in aqueous or acetic acid solution. Thus, an aliquot of the vinyl alcohol was added dropwise to a rapidly stirred ice cold aqueous or acetic acid solution containing 2 molar equivalents of hydrogen bromide. When addition was complete, stirring was continued for 20 minutes and then the reaction mixture was poured into an excess of ice cold percent sodium carbonate solution, ex-

tracted with diethyl ether and washed to neutrality with water. After drying the ethereal extracts over sodium sulfate and removal of the solvent in vacuo; the allylic bromides were obtained in nearly quantitative yield.

CH; R CH; R

Another series of compounds in which the terpenoid carbon chain was one carbon longer were prepared in a similar manner except that the bromides were prepared by a continuation of the Julia synthesis as follows:

R a.- iecai anzse fiis a Compounds of the general formula R is a straight chain alkyl containing from 1 to 2 carbon atoms such as Cl-l CH Cl-l x is a number from I to 2; and

A is

CH3 CH3 in which n is 0 to 3; were synthesized by coupling the foregoing bromides with the respective alcohols of A to form the corresponding ethers by refluxing the bromides or stirring at room temperature for several hours with a slight molar excess of the alcohols and a base such as powdered potassium hydroxide or potassium teritary butoxide in an anhydrous solvent-such as diethyl ether, dimethoxyethane or dimethyl formamide. Alternatively, the reactants were sealed in a small reaction bomb and place in an oven at C for 2-4 hours.

The reaction mixture was then diluted with water and extracted several times with hexane. The hexane extracts were combined and washed to neutrality with water. The hexane portion was dried over sodium sul fate and the solvent removed in vacuo to yield the crude ethers.

CH: R

The crude ethers obtained from the foregoing reactions were purified by chromatography over florisil. The crude material was put on a fluorisil column (30 gm florisil/gm crude material) in hexane and eluted stepwise with increasing concentrations of diethyl ether in hexane. Purity was determined by gas-liquid chromatography and infra-red spectroscopy to be greater than 99 percent.

Compounds of the general formula R is a straight chain alkyl containg from 1-2 carbon atoms such as CH CH CH x is a number from i to 2; and

E is --CH CO0(CH ),,CH or The primary halides of E, (Br CH COO( CH CH or were coupled with the terpenoid alcohols under basic conditions in a reaction bomb, under reflux, or by stirring at room temperature for an extended period of time.

C: R .a:i=c ;t@ ii.=9 w. The crude ethers were purified by chromatography over florisil as previously described. Purity was determined by gas-liquid chromatography and infra-red spectroscopy to be greater than 99 percent. Compounds of the general structure R CH3 Y(CH2): C: CH (CH1) -O-Jl H-O (CH1) CH3 wherein Y is R=Straight chain alkyl containing from 1-2 carbon atoms such as CH CH CH x is a number from 1 to 2; and

n is a number from 0 to 3 were prepared by stirring the terpenoid alcohols for 2 hours at room temperature with the appropriate vinyl Purity was ascertained by gas-liquid chromatography and infrared spectroscopy to be greater than 99 percent.

The compounds and their epoxides prepared by the above procedures are shown in Table 1.

Although the general procedures just described are undoubtedly adequate for those skilled in the art, the following examples further illustrate the preparation of compounds within the scope of each of the general structures shown above.

Synthesis of Compound 49 in Table I -Br IIOCzHiOCd-h Epoxidation of Compound 49 in Table I ether in the presence of a catalytic amount of hydrochloric acid.

The reaction was complete in 1 hour and the reaction mixture was extracted with diethyl ether and washed successively with 5 percent aqueous sodium carbonate and water. The ethereal extract was dried over anhydrous sodium sulfate. The crude product was isolated by evaporation of the solvent in vacuo.

The desired compounds were purified by column chromatography over florisil as previously described. Purity was determined by gas-lipid chromatography and infrared spectroscopy to be greater than 99%.

All of the ethers prepared by the foregoing syntheses were then epoxidized by stirring them in an organic solvent such as benzene. chloroform or methylene chloride during the addition of a slight molar excess of an epoxidizing agent such as m-chloro perbenzoic acid.

Epoxidation occurred selectively at the terminal double bond within a few minutes to one hour. The reaction mixture was washed with 5 percent sodium carbonate and then with water to neutrality, and dried over sodium sulfate. Solvent was removed in vacuo.

The epoxides were purified by chromatography over florisil as previously described.

Dissolved 4 g. of the Comp' uhm in 50 ml. CH Cl and with stirring added 3.2 g. m-chloroperbenzoic acid in aliquots. Stirred 30 min. and then made the solution basic with 10 percent aqueous sodium carbonate. Stripped off the solvent in vacuo. Residue was dissolved in diethyl ether and washed in a separatory funnel with 10 percent sodium carbonate 2X, and water 2X. Dried organic layer over anhydrous sodium sulfate. Stripped off solvent in vacuo. Crude epoxide yield was 3.8 gm. Fractionation of the crude epoxide over 60 gm. of florisil by stepwise elution with increasing concentrations of diethyl ether in hexane gave 3.0 g. pure epoxide. (Compound No. 57)

Synthesis of Compound 65 in Table II CH3 CH3 0 \O jm jiessia ii c Dissolved 1 gm. of Compound 81 in tion with increasing concentrations of diethyl ether in hexane gave 1.9 g. of pure Compound 65.

Epoxidation of Compound 65 in Table ll Dissolved 1.3 g. of Compound 65 in's'o mi. CH2C12 as washed in a separatory funnel with sodium car,

bonate 2X and with water 2X. Dried over anhydrous sodium sulfate. Crude epoxide, Compound 73, was 1.3

The crude epoxide was fractionated by column chromatography as specified for Compound 65. Yield of pure epoxide, Compound 73, was 950 mg. (Compound 73) Synthesis of Compound 81 in Table l Stirred 5 gm geraniol with 3.5 gm. potassium tertbutoxide in 50 ml. dimethoxyethane for 30 minutes. Added to above 5.8 g. of methyl bromoacetate and stirred at room temperature for 16 hrs. Reaction mixture dissolved in 200 ml. diethyl ether and washed in a separatory funnel with water 3X. Organic layer dried over anhydrous sodium sulfate. Stripped off solvent in vacuo. Yield of crude Compound 8] was 7.3 gm.

The crude ether was chromatographed on a column containing 150 gm. of florisil. Elution with increasing concentrations of diethyl ether in hexane gave a pure fraction containing 1.4 gm. of Compound 81.

Epoxidation of Compound 89 in Table l 79 .QQQ 3 25 ml. of CHC] Hexane (3-2) containing 0.4 gm. sodium bicarbonate with stirring in an ice bath. To this was added dropwise 1.0 gm. m-chloroperbenzoic acid in 25 ml. of CHCh-Hexane (32). After addition, stirring in the ice bath was maintained for min. Sodium sulfite was added to destroy any excess peracid. The reaction mixture was dissolved in about 200 ml. of diethyl ether 5 and washed in a separatory funnel with '10 percent aqueous sodium carbonate 2X and water 2X. Organic layer was dried over anhydrous sodium sulfate and the solvent stripped off in vacuo. Yield'of crude Compound 89 was 1.26 gm. Y

The crude Compound 89 was fractionated over 3 gm. of florisil as specified for Compound 81 and 770 mg. of pure Compound 89 was obtained. Analysis by gas-chromatography and infrared. (Compound 89) Synthesis of Compound 1 13 in Table l Dissolved 5 g. geraniol in 50 ml. dimethoxyethane containing 3.5 g. potassium tert-butoxide with stirring for 30 min. Added 4.4 g. epibromohydrin and stirred at room temperature for 3 hrs. Filtered, dissolved in about 250 ml. diethyl ether and washed with water 3X in a separatory funnel. The organic layer was dried over anhydrous sodium sulfate and the solvent stripped off in vacuo. Yield of crude ether was 7.6 gm. The crude ether was fractionated by column chromatography over 150 gm. of florisil. Stepwise elution with increasing concentrations of ether in hexane gave 2.24 gm. of pure Compound 1 l3.

Epoxidation of Compound 113 in Table 1 )VV 0cmo ;Em .w A I OCHsC'H H:

Dissolved 2.24 g. of Compound 113 in 50. m1. CH Cl and with stirring added 2.2 g. m-chloroperbenzoic acid in aliquots. Stirred an additional 30 min., made basic with 10 percent aqueous sodium carbonate, dissolved in 200 ml. diethyl ether and washed with 10 percent aqueous sodium carbonate 2X and with water 2X in a separatory funnel. Organic layer dried over anhydrous sodium sulfate. Yield of crude Compound 121 was 2.0

gm. Column chromatography of Compound 121 over 60 gm. florisil by stepwise elution with increasing concentrations of diethyl ether in hexane gave 713 mg. of

pure Compound 121. Analysis by gas-chromatography and infrared. (Compound 121) Synthesis of Compound in Table l Geraniol (10 gm.) in 25 ml. diethyl ether was added dropwise to 14 g. ethyl vinyl ether containing 1 drop of concentrated HCl. After addition, stirring was maintained for 2 hrs. in a warm water bath (ca. 50C.).

The reaction mixture was dissolved in 200 ml. of diethyl ether and washed in a separatory funnel with 5 percent aqueous sodium carbonate IX, and water 3X. The organic layer was dried over anhydrous sodium sulfate. The solvent was stripped off in vacuo. The crude acetal yield was 14.5 gm.

Filtration of 5 gm. of the acetal in hexane through a column containing gm. of florisil gave a quantitative return of 5 gm. of pure acetal Compound 145. Purity ascertained by gas-chromatography and infrared analysis.

- Epoxidation of Compound 145 in Table l To a stirred solution of 5 gm. of Compound 145 in 100 ml. hexane was added dropwise 4.94 gm. mchloroperbenzoic acid dissolved in 100 ml. CH CI After addition, stirring was continued for 20 min. Excess peracid was destroyed with sodium sulfite. The reaction mixture was made basic with percent aqueous potassium hydroxide and the solvent stripped off in vacuo. The residue was dissolved in diethyl ether and washed in a separatory funnel with 5% aqueous potassium hydroxide IX and with water 3X.

Organic layer was dried over anhydrous sodium sulfate and the solvent stripped off in vacuo. Yield of crude Compound 153 was 5.0 gm.

Fractionization of 5.0 gm. of Compound 153 by column chromatography over 100 gm. of florisil by stepwise elution with increasing concentrations of diethyl ether in hexane gave 3.0 gm. of pure Compound 153. Analysis by gas-chromatography and infrared. (Compound 153).

The morphogenetic effects of some of the compounds in the Tenebrio genitalia assay (Life Sciences 4, 2,323-3l, 1965) are shown in Table ll.

Topical application to Tenebrio pupae of as little as nanograms (0.01 pg) of several compounds (i.e. 25, 26, 28, 57, 73) resulted in the retention of complete pupal genitalia after the ultimate molt toward the adult beetle. Topical application of 100 nanograms (0.1 pg) resulted in the development of pupal-adult intermediates.

Topical application of somewhat greater amounts of compounds 76, 89, 121, 153, were required to induce retention of pupal genitalia and/or produce pupal-adult intermediates in Tenebrio. In all cases the affected insects were unable to form normal adults and died during or shortly after their ultimate molt without significant feeding and without any reproduction.

Table III shows the effects of compounds 25, 26, 28, 57, 73, 8 l, 89, [53, on the Mexican bean beetle. Topical application of nanogram to microgram quantities of these compounds prevents normal adult development and the insects die during the ultimate molt. Topical treatment of Mexican bean beetle eggs with extremely dilute acetone solutions of these compounds caused severe reduction in egg hatch.

Table IV shows the morphogenetic effects of compounds 25, 26, 28, 57, 73, 89, 121, 153, on Tenebrio after exposure of the pupae to the vapors of these compounds. These results exemplify the potential use of the compounds as fumigants.

TABLE I Synthesized Terpenoid Ethers and Their Epoxides 20 u 0CH3CHz-OCH2CHJ V CH1CHr-O(CH;);CHQ

\ O CHgCH: O(CHz) CHa cmcm-ownmcm Q FW OCHiCHI O( Q)J HS i W o among-acumen:

VOCHzCHzO (CH2) 30113 OCHzCHg-O ((1H,) CH3 O l 1'-O( 1)3 J OCH3CHr-O (CH1) QCHJ OCHICH1O(CH2)3CH3 -OCHzCHzO (CH2) QCHJ OCH1CH1-O (CH1) 30H;

OCH1CH1O (CH1) 3CH3 CH /CH:

CH3 CH 168 Table 111 1 Reduction in Adult Emergence and Egg Hatch of Mexican O CH-OCHaCHzCHa Bean Beetle EpiIac/mu \arireslix 159 CH Compound Micrograms of Compound PPM of Compound Required to cause 907: Required to cause NV- HOQH2CH!CHK Number in Reduction in adult 90% Reduction in O Table l Emergence Egg Hatch 25 0.1 1.0 170 26 0.1 10.0 CH3 28 0.01 1.0 g: 57 0.l [00.0 0 HO CI'IZCII'JCI'II! 73 0.1 l().() WV 81 10.0 100.0 0 89 100.0 100.0 l5? ().l 1.0 171 i H3 Topical treatment of 2-day old prcpupae with an acetone solution of compound. NVO I{O CH2CII2 I'I3 Topical treatment by dipping egg masses in an acetone solution of compound. O/ An acetone control conducted for each of the above treatments showed that the 172 solvent contributed nothingto the effect of the compounds 0 H-O CHQCHZCH Table 1v O/ 173 Morphogentic Effects of Representative Compounds on I CH3 Tt'liehrio pupae by Fumigation.

l O CH-O CHzCHzCHa Compound Micrograms of Compound Required to Produce Pupal-Genitalia and Pupal- Number in Adult intermediates by Vapor Expo- 174 Table I sure I l 25 0.1 5.0 /i\ 5 20 0.1 5.0 o IIOCH2CII2CH3 28 0.1 5.0 O 57 0.1 5.0 73 0.] 5.0 a9 0.1 50 I2] l.() -l0.0 CH3 153 10-100 1 CHO CHYCHZCHK Compounds were spread over the lid ofa IOU mm diameter petri dish in a small volume of acetone and after evaporation of the acetone the lid was placed over the 176 bottom of the petri dish containing newly moltcd Tt'nuhriu pupae, The pupae were U therefore exposed-only to the vapors and did not come in Contact with the compound directly. The insects were left in the dish until the underwent the final CH 0 molt toward the adult.

3 l o CH-O CHzCHzCH;

' h T I claim:

1. A method of controlling the maturation of insects selected from the group consisting of Tenebrio molitur T, bl H (L.) and Epilachna varivesti's comprising contacting 6 said insects at an immature stage of growth with an ef- M h Eff f R C fective maturation inhibiting amount of a compound of orp ogenetic ects o eprescntative ompounds in the 'It'm-hriu Gt-niluliu A.1'.\'t1 the formula Compound Micrograms of Compound Required to Number Produce the Indicated Morphogenetic Effects CH3 1 in Pupal-Adult I Table l Intermediates Pupal Genitalia 2)2O Z)x O 2)2 I)11 3 25 0.1 0.01 mm 26 O. 0.0] 28 0m 1n whlch R and R are stratght chain alkyls contammg 57 0.1 0.01 from I to 2 carbon atoms; x is a number from 1 to 2;

3'? and n is a number from O to 3. I 89 100. 1, 2. The method of claim 1 in which the juvenile horigg g 60 mone mimicking compound is applied topically.

" Pupal adult intermediates represent an intermediate in which the insect molts to a monster with an essentially pupal abdomen and an adultoid head and thorax.

Papal genitalia 3. The method of claim 1 in which the juvenile hormone mimicking compound is applied as a fumigant.

4. The method of claim 1 in which the juvenile hor- 'mone mimicking compound is applied orally.

5. The method of claim 1 in which the juvenile horrefcrs to the effect in which the insect is nearly adult but retains mone mimicking compound is applied as a solute in ac- CH: R

etone- R( 3=CH(CH;) CH(CHz)r-(CH:)r0(CHQ CH 6. A method of preventing the hatching of eggs of in- I sects Selected 9 the group consisting of Tenebrio in which R and R are straight chain alkyls containing molitor (L.) and Epilaclma varivestis comprising applyfrom 1 to 2 carbon atoms; x is a number f 1 to 2; ing to said insect eggs an effective egg hatch preventive and n is a number from 0 to 3' amount of a compound of the formula 

1. A METHOD OF CONTROLLING THE MATURATION OF INSECTS SELECTED FROM THE GROUP CONSISTING OF TENEBRIO MOLITOR (L.) AND EPILACHNA VARIVESTIS COMPRISING CONTACTING SAID INSECTS AT AN IMMATURE STATE OF GROWTH WITH AN EFFECTIVE MATURATION INHIBITING AMOUNT OF A COMPOUND OF THE FORMULA
 2. The method of claim 1 in which the juvenile hormone mimicking compound is applied topically.
 3. The method of claim 1 in which the juvenile hormone mimicking compound is applied as a fumigant.
 4. The method of claim 1 in which the juvenile hormone mimicking compound is applied orally.
 5. The method of claim 1 in which the juvenile hormone mimicking compound is applied as a solute in acetone.
 6. A method of preventing the hatching of eggs of insects selected from the group consisting of Tenebrio molitor (L.) and Epilachna varivestis comprising applying to said insect eggs an effective egg hatch preventive amount of a compound of the formula 